[en] Purpose: Salivary duct carcinoma (SDC) is a rare and aggressive salivary gland cancer subtype with poor prognosis. The mutational landscape of SDC has already been the object of several studies, however little is known regarding the functional genomics and the tumor microenvironment despite their importance in oncology. Our investigation aimed at describing both the functional genomics of SDC and the SDC microenvironment, along with their clinical relevance. Methods: RNA-sequencing (24 tumors), proteomics (17 tumors), immunohistochemistry (22 tumors), and multiplexed immunofluorescence (3 tumors) data were obtained from three different patient cohorts and analyzed by digital imaging and bioinformatics. Adjacent non-tumoral tissue from patients in two cohorts were used in transcriptomic and proteomic analyses. Results: Transcriptomic and proteomic data revealed the importance of Notch, TGF-β, and interferon-γ signaling for all SDCs. We confirmed an overall strong desmoplastic reaction by measuring α-SMA abundance, the level of which was associated with recurrence-free survival (RFS). Two distinct immune phenotypes were observed: immune-poor SDCs (36%) and immune-infiltrated SDCs (64%). Advanced bioinformatics analysis of the transcriptomic data suggested 72 ligand-receptor interactions occurred in the microenvironment and correlated with the immune phenotype. Among these interactions, three immune checkpoints were validated by immunofluorescence, including CTLA-4/DC86 and TIM-3/galectin-9 interactions, previously unidentified in SDC. Immunofluorescence analysis also confirmed an important immunosuppressive role of macrophages and NK cells, also supported by the transcriptomic data. Conclusions: Together our data significantly increase the understanding of SDC biology and open new perspectives for SDC tumor treatment. Before applying immunotherapy, patient stratification according to the immune infiltrate should be taken into account. Immune-infiltrated SDC could benefit from immune checkpoint-targeting therapy, with novel options such as anti-CTLA-4. Macrophages or NK cells could also be targeted. The dense stroma, i.e., fibroblasts or hyaluronic acid, may also be the focus for immune-poor SDC therapies, e.g. in combination with Notch or TGF-β inhibitors, or molecules targeting SDC mutations.
Disciplines :
Oncology
Author, co-author :
Alame, Melissa; Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM, Parc Euromédecine, 208 rue des Apothicaires, 34298 Montpellier, France ; Biological Hematology Department, CHU Montpellier, Hôpital Saint Eloi, 34275 Montpellier, France ; Université de Montpellier, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093 Montpellier, France ; Institut Régional du Cancer Montpellier (ICM), Parc Euromédecine, 208 rue des Apothicaires, 34298 Montpellier, France
Cornillot, Emmanuel; Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM, Parc Euromédecine, 208 rue des Apothicaires, 34298 Montpellier, France ; Université de Montpellier, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093 Montpellier, France ; Institut Régional du Cancer Montpellier (ICM), Parc Euromédecine, 208 rue des Apothicaires, 34298 Montpellier, France
Cacheux, Valère; Biological Hematology Department, CHU Montpellier, Hôpital Saint Eloi, 34275 Montpellier, France ; Université de Montpellier, Faculté de Médecine, 2 rue école de Médecine, 34060 Montpellier, France
Tosato, Guillaume; Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM, Parc Euromédecine, 208 rue des Apothicaires, 34298 Montpellier, France ; Université de Montpellier, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093 Montpellier, France ; Institut Régional du Cancer Montpellier (ICM), Parc Euromédecine, 208 rue des Apothicaires, 34298 Montpellier, France
Four, Marion; Biopathology Department, CHU Montpellier, Hôpital Gui De Chauliac, 34000 Montpellier, France
De Oliveira, Laura; Biopathology Department, CHU Montpellier, Hôpital Gui De Chauliac, 34000 Montpellier, France
Gofflot, Stéphanie ; Centre Hospitalier Universitaire de Liège - CHU > > Biothèque Hospitalo-Universitaire de Liège (BHUL)
Delvenne, Philippe ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Turtoi, Evgenia ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Labo de recherche sur les métastases ; Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM, Parc Euromédecine, 208 rue des Apothicaires, 34298 Montpellier, France ; Institut Régional du Cancer Montpellier (ICM), Parc Euromédecine, 208 rue des Apothicaires, 34298 Montpellier, France ; Université de Montpellier, 163 rue Auguste Broussonnet, 34090 Montpellier, France
Cabello-Aguilar, Simon; Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM, Parc Euromédecine, 208 rue des Apothicaires, 34298 Montpellier, France ; Institut Régional du Cancer Montpellier (ICM), Parc Euromédecine, 208 rue des Apothicaires, 34298 Montpellier, France ; Université de Montpellier, 163 rue Auguste Broussonnet, 34090 Montpellier, France
Nishiyama, Masahiko; Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Gunma, Japan
Turtoi, Andrei ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Labo de recherche sur les métastases ; Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM, Parc Euromédecine, 208 rue des Apothicaires, 34298 Montpellier, France ; Institut Régional du Cancer Montpellier (ICM), Parc Euromédecine, 208 rue des Apothicaires, 34298 Montpellier, France ; Université de Montpellier, 163 rue Auguste Broussonnet, 34090 Montpellier, France
Costes-Martineau, Valérie; Université de Montpellier, Faculté de Médecine, 2 rue école de Médecine, 34060 Montpellier, France ; Biopathology Department, CHU Montpellier, Hôpital Gui De Chauliac, 34000 Montpellier, France
Colinge, Jacques; Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM, Parc Euromédecine, 208 rue des Apothicaires, 34298 Montpellier, France ; Institut Régional du Cancer Montpellier (ICM), Parc Euromédecine, 208 rue des Apothicaires, 34298 Montpellier, France ; Université de Montpellier, Faculté de Médecine, 2 rue école de Médecine, 34060 Montpellier, France
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